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Volume 14 No. 07
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Accepted Papers





Scientific Investigations

Continued Presence of Period Limb Movements During REM Sleep in Patients With Chronic Static Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS)

Jonathan D. Santoro, MD1; Jennifer Frankovich, MD2; Sumit Bhargava, MD3
1Division of Child Neurology, Department of Neurology, Lucile Packard Children's Hospital at Stanford, Palo Alto, California; 2Division of Allergy, Immunology & Rheumatology, Department of Pediatrics, Lucile Packard Children's Hospital at Stanford, Palo Alto, California; 3Division of Pediatric Pulmonary and Critical Care, Department of Pediatrics, Lucile Packard Children's Hospital at Stanford, Palo Alto, California

ABSTRACT

Study Objectives:

A major component of pediatric acute-onset neuropsychiatric syndrome (PANS) is disruption of sleep. These disturbances have been reported in the acute phase of diagnosis but it is unknown if these sleep disruptions persist, especially in patients with chronic static symptoms. This retrospective chart review sought to review polysomnography (PSG) tests of patients in whom PANS has been clinically diagnosed in order to assess sleep architecture, periodic limb movements, and presence of rapid eye movement (REM) sleep without atonia (RSWA) after a chronic static course of symptoms, which were refractory to immunomodulatory interventions.

Methods:

Patients were retrospectively identified through the PANS clinic at our institution and had to have fully completed a PSG study and be younger than 18 years. PSG with video were reviewed and scored based on established criteria.

Results:

We identified 9 patients who met inclusion criteria. The median time from presentation to PSG was 4 years. This study identified PSG-measured periodic limb movement index (PLMI) > 5 events/h in REM sleep in 7 of 9 patients. Two patients with elevated PLMI also demonstrated RSWA, although neither fit a clinical diagnosis of REM sleep behavior disorder. This cohort also demonstrated increased onset of REM sleep (median 134 minutes), insomnia (median total sleep time of 389 minutes), and decreased sleep efficiency (77%).

Conclusions:

This study identifies continued sleep disturbances in patients with refractory PANS symptoms several years after diagnosis and treatment. Continued sleep disturbances after presentation and treatment in patients with chronic static PANS may be a contributing factor in prolonged symptomatology of this disease process.

Citation:

Santoro JD, Frankovich J, Bhargava S. Continued presence of period limb movements during rem sleep in patients with chronic static pediatric acute-onset neuropsychiatric syndrome (PANS). J Clin Sleep Med. 2018;14(7):1187–1192.


BRIEF SUMMARY

Current Knowledge/Study Rationale: Patients with pediatric acute-onset neuropsychiatric syndrome (PANS) have been shown to have sleep dysregulation with previously established elevations in periodic limb movements and rapid eye movement sleep without atonia during early phases of the disease.

Study Impact: This study identifies continued presence of periodic limb movements and rapid eye movement sleep without atonia in patients with chronic static PANS. Continued sleep disturbances after presentation and treatment in patients in chronic static PANS may be a contributing factor in prolonged symptomatology of this disease process.

INTRODUCTION

Pediatric acute-onset neuropsychiatric syndrome (PANS) is defined as abrupt (overnight) onset of severe obsessive-compulsive disorder (OCD) symptoms and/or eating restriction in conjunction with other neuropsychiatric symptoms, including anxiety, behavioral regression, irritability/aggression, motor abnormalities, and urinary disturbances.1 Additionally, a major component of this syndrome includes poorly defined disruptions of sleep that can include insomnia, nightmares, restlessness, and reverse cycling. Sleep complaints have been appreciated in the literature as affecting up to 84% of patients.24

Prior studies have revealed a number of sleep disruptions including insomnia, rapid eye movement (REM) sleep motor disinhibition, and frequent nocturnal arousals.24 It is unknown what roles sleep disturbances play in the recognized symptoms and natural history of PANS or how long the sleep disturbance persists. Although uncommon in children, periodic limb movement disorder (PLMD) has been reported in pediatric populations but definitive criteria have been variable and largely based on studies in adults.57 This entity has been reported in children with PANS during the initial phase of the disease process, although no long-term studies have investigated its sustained prevalence in patients who have chronic static clinical courses. Interestingly, PLMD has been associated with REM sleep without atonia (RWSA) in which phasic and tonic muscle activity are noted during REM sleep where atonia is expected.8,9 Although the exact pathophysiology of these sleep disorders in children is unknown, the presence of RSWA has been reported in neurodegenerative disease, Tourette syndrome, posttraumatic stress disorder, and depression.912

Although prior studies have identified PLMD in the acute phases of PANS, no studies have investigated longer-term evidence of this pathology.4 This study sought to retrospectively review PSG reports of patients in whom a clinical diagnosis of PANS was made at a delayed time point after symptom onset in patients with chronic static clinical courses and observe if they displayed evidence of PLMD and/or RSWA.

METHODS

Subjects With PANS

Consecutive patients were identified retrospectively in accordance with Stanford University IRB approval following diagnosis of PANS at the Lucile Packard Children's Hospital at Stanford's multidisciplinary PANS clinic and the completion of a PSG for any sleep-related disturbance from March 2014 to March 2016. Data were extracted from a multidisciplinary PANS clinic notes, pulmonary/sleep medicine clinic notes, psychiatry clinic notes, radiology reports, and PSG study review. Patients carrying a variety of comorbid conditions were included with the exception of epilepsy, previously diagnosed sleep disorders, and disorders affecting the airway or ability to ventilate. No patients in our cohort had neuromuscular disease, known neurodegenerative disease, or cortical malformation that could alter sleep architecture.

Polysomnography

Patients included had to fully complete a PSG study and be younger than 18 years. All patients had to spend at least 15% of their total sleep time in REM sleep for inclusion. Studies were conducted as an all night (although in one case daytime due to sleep phase reversal) examination in accordance with the standards defined by the American Academy of Sleep Medicine (AASM) without electroencephalogram monitoring but with chin electromyography applied. Software utilized during PSG collection and analysis was Sandman NT (Nellcor Puritan Bennett, Ottawa, Ontario, Canada). PSG with video was reviewed and scored based on previously established criteria for periodic limb movement and RSWA (Appendix A in the supplemental material).8,13,14 The definition of abnormal periodic limb movement index (PLMI) was ≥ 5.0 events/h, consistent with existing pediatric literature.68

RESULTS

A total of 15 patients were identified for inclusion in this study.

Using the exclusion criterion listed, this cohort was narrowed down to 9 patients. Four patients were excluded for presence of previously diagnosed neurologic disorders, one patient was excluded for facial dysmorphia that could complicate assessment of airway, and one patient was excluded for paroxysmal events concerning for seizures. No patients were excluded for inability to obtain 8 hours of sleep or < 15% of total sleep time in REM sleep. Presence of movement disorders was not clinically assessed prior to the sleep study. Evidence of movement disorders was not observed on video during the PSG.

Patient demographics and PANS clinical courses are listed in Table 1. The median time from initial symptoms to PSG was 4 years. The median age of our cohort was 8 years (range 4–14 years); there were 7 males and 2 females. At the onset of symptoms, all patients had severe OCD and/or eating restriction related to OCD and profound sleep disturbances. Other common symptoms include: agitation (n = 8), aggression (n = 3), behavioral regression (n = 5), chorea (n = 6), and tics (n = 7). Patients were treated with nonsteroidal anti-inflammatory drugs (n = 1), antibiotics (n = 5), steroids (n = 5), and intravenous immunoglobulin (n = 9), but all had eventual progression to chronic static disease state. The median time to treatment from initial symptom onset in this cohort was 9.5 months. With regard to preexisting sleep complaints, insomnia was the most common symptom and was reported in almost all patients (8/9). Other clinical sleep pathology included subjective report of restlessness in 4 patients, frequent nocturnal awakenings/arousals in 3 patients, sleep paralysis in one patient, and hypersomnia in 1 patient. There were no patients who had snoring or apnea endorsed by personal or caregiver history. Of patients with documented sleep histories prior to presentation, 3 of 5 patients were noted to have a history of sleep terrors when aged younger than 5 years. Prior physical examination abnormalities were noted in 8 patients (89%), with choreiform movements noted in 6 patients (67%). At the time of PSG, no patients had an active chorea nor any focal neurologic findings. Magnetic resonance imaging of the brain was performed in 4 patients with no lesions providing an explanation for the patient's symptoms. Electroencephalography was performed in 2 patients (patients 7 and 8), noting generalized, but rare, epileptiform discharges without seizure activity.

Patient demographics, PANS clinical course, and prior neurodiagnostic studies.

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Table 1

Patient demographics, PANS clinical course, and prior neurodiagnostic studies.

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Routine PSG data are reported in Table 2. The median sleep efficiency was 82% in all patients, although the interquartile range was 65–91. REM sleep latency was slightly elevated with a median of 145 minutes. Patients on average spent 0.4% of sleep in stage N1 sleep, 43.4% in stage N2 sleep, and 35.1% in stage N3 sleep. Patients spent a mean of 21.1% of sleep in stage R sleep. Arousal data are reported in Table 3. In general, arousals were within expected range for age with a median arousal index (AI) of 13.8 events/h. This was further broken down to non-rapid eye movement (NREM) sleep AI and REM sleep AI, which were similar in medians of 12.77 and 12.41 events/h, respectively. Spontaneous and respiratory AI were within normal limits for age, although spontaneous arousals occurred more frequently in NREM (median value 9.89 events/h) compared to REM sleep (median value 6.04 events/h), which was the inverse of respiratory arousals, which occurred less frequently in NREM (median value 0.31 events/h) compared to REM sleep (median value 0.72 events/h). The apnea-hypopnea index (AHI) had a median value of 2.17 events/h with an interquartile range of 0.8–2.5 events/h. There was only one patient with an AHI above 5.0 events/h (patient 7). No arousals were associated with choreiform movements nor were there any complex dream enactments recorded on video.

PSG data.

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Table 2

PSG data.

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Arousal indices by patient.

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Table 3

Arousal indices by patient.

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Periodic limb movement data is reviewed in Table 4. Overall, PLMI was elevated in REM sleep in 7 patients (median 6.9 events/h). Patients had a median PLMI in NREM sleep of 9.0 events/h. Periodic limb movements that initiated arousals were elevated in REM but not NREM sleep, with median values of 2.1 and 8.0 events/h respectively. Means for these values were 2.6 and 4.2 events/h, respectively, with one patient having a periodic limb movement AI greater than 5.0 events/h. RSWA was noted in 2 patients in this study on manual review of PSG data. Of the 7 patients with elevated PLMI in REM sleep, 6 had PLMI caused by arousals, with an average of 68% of all events being associated with electrographic arousals. These patients both had elevated PLMI in REM sleep (8.8 and 11.43 events/h respectively) but demonstrated mild-moderate movements of the extremities and increased electromyogram recordings in the chin with no overt dream enactment, vocalizations, or coordinated movements out of bed. The presence periodic limb movements in patients with elevated PMLI was associated with electrographic arousal in all patients, which was deemed consistent with a diagnosis of PLMD by the authors in accordance with AASM standards.7,8 No movements reviewed were consistent with a comorbid movement disorder or choreiform movement.

PLM and REM sleep behavior disorder indices.

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Table 4

PLM and REM sleep behavior disorder indices.

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DISCUSSION

This manuscript characterizes the disordered sleep of patients carrying a diagnosis of chronic static PANS a median of 4 years after onset of symptoms. In reviewing our cohort of patients, increased PLMI in REM sleep is consistent with a diagnosis of PLMD based on previously established criteria, noted in 7 of 9 patients.4,7,8 When compared to a control populations in which no comorbid illnesses were present, these patients were noted to be above the expected range, which is also consistent with previously established criteria although only mildly so.57 Interestingly, 2 patients within this group also were noted to have clinical evidence of RSWA in review of video recorded PSG. Patients who demonstrated an elevated PLMI (or RSWA) were not observed to have an elevated AHI with the exception of patient 7, who also had a normal PLMI, which has previously been associated with PLMD as a possible confounding variable for arousal.15,16 Similarly, unremarkable AI in multiple domains exclude other nonorganic etiologies to the abnormalities reported.

Patients in our cohort were also noted to have subjective sleep complaints that matched PSG findings. Insomnia was the most commonly reported sleep issue and was reflected in a low mean sleep duration of 380 minutes and diminished sleep efficiency of 77%. Additionally, the subjective complaint of restless sleep and frequent nocturnal awakenings matched our cohort in that elevated arousals, both in and out of REM sleep and both with and without periodic limb movements, were observed. Patients also demonstrated mildly increased onset of REM sleep at a median of 145 minutes, although time spent in REM sleep and median number of REM cycles was noted to be within normal ranges, making the significance of this finding unclear. Interestingly, overall sleep architecture and staging frequencies were preserved in the group.

The primary goal of this retrospective review was to identify the presence of PLMI in patients with chronic static PANS and our findings were positive, as a large portion of our reviewed PSG tests demonstrated evidence of PLMD. Although rates of PLMD have previously been reported in this population, this is the first report of association between PANS and PLMD in the nonacute period. The results of this study are not entirely novel but add to the existing literature of prominent sleep disturbances in patients with PANS. Specifically, the authors found it interesting that delays in treatment and chronic refractory PANS symptomatology were also associated with concurrent sleep disorders. Since limiting acceptance of patients with PANS into our interdisciplinary clinic to patients with new onset (< 3 months of symptoms) and no underlying psychiatric disease we have anecdotally (unpublished data) demonstrated that PANS symptoms quickly abate with immunotherapy, although sleep studies have not been repeated as subjective sleep disruptions have improved in this group. Prospective data tracking these disturbances longitudinally in patients treated in the acute period (ie, within 3 months of symptom onset) would be of great interest to determine whether improved PANS symptom control coincides with improvements in sleep disturbances if present.

This study was biased with regard to the overrepresentation of males (three-fourths of the cohort), which may skew both clinical phenotypes (a potential contributor to higher rates of emotional lability and aggression) and sleep characteristics. Our study is limited in the assessment of sleep at one point in time, after therapy for PANS has been started and several years after the onset of symptoms. In order to better assess whether the sleep abnormalities appreciated in our study are truly associated with PANS symptoms/phenotype, it would be ideal to obtain sleep studies in patients with a relapsing-remitting disease course and compare PLMI and RSWA in both phases of the illness (during the relapse when patients are symptomatic from PANS and during remission when neuropsychiatric symptoms have abated. This study was further limited by the small number of patients who were referred for PSG. Patients in whom PANS symptoms rapidly resolve after early intervention (treatment of known infection plus immunomodulatory therapy) are not referred for sleep studies.17,18 Additionally, we do not refer patients for PSG if they have severe psychiatric symptoms, rage, or other behaviors that would limit the ability to participate in the PSG. Pediatric literature confirms the use of a PLMI cutoff point of ≥ 5.0, although this numerical point has been largely based on studies on adult patients.58,15,16 Given the retrospective nature of this study we think that this value is the best control possible for assessment against our patients with PANS, especially given the known association with comorbid conditions and presence of PLMD.7,913

In summary, our study presents the novel finding of long-term elevations in PLMI in patients in whom PANS has been diagnosed, indicating the possible presence of PLMD years after diagnosis and treatment. This finding is noted to be elevated when compared to defined values of expected PLMI < 5 in prior studies.47 Although it is difficult to extrapolate the true effect of this finding on the patient's neuropsychiatric diagnosis and prognosis, it is clear that the effects of PLMD may interfere with or worsen the patients' symptoms. Although two patients had evidence of RSWA, it is difficult to determine whether these patients truly meet criterion for REM sleep behavior disorder or what effect this has on the consideration of diagnosis in this small cohort.19 We recommend further prospective investigation into the sleep disturbances of patients with PANS and long-term tracking of the patient's clinical symptoms as treatments are administered.

DISCLOSURE STATEMENT

All authors have seen and approved this manuscript in its full form. The authors report no conflicts of interest.

ABBREVIATIONS

AHI

apnea-hypopnea index

OCD

obsessive-compulsive disorder

PANS

pediatric acute-onset neuropsychiatric syndrome

PLMD

periodic limb movement disorder

PLMI

periodic limb movement index

PSG

polysomnography

REM

rapid eye movement

RWSA

REM sleep without atonia

ACKNOWLEDGMENTS

The authors are thankful for the efforts of Talia Mahoney, Mark Freeman, and Collin Leobold in the PANS Clinic and Research Group, and the department of Pulmonology and Child Neurology at the Lucile Packard Children's Hospital at Stanford.

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